Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Driven by common disease common variants hypothesis, genome-wide association studies only identified a number of common susceptibility loci that explained a small portion of CRC heritability. The goal of this project is to identify rare genetic variants with intermediate effect size that predispose individuals to colorectal cancer through a next generation sequencing approach. This proposal builds upon a rich resource of the large CRC patient population at MD Anderson Cancer Center and a population-based resource at University of Utah. There are four specific aims. The first aim is to identify novel susceptibility genes for CRC by conducting whole exome sequencing in 500 cases and 500 controls from MD Anderson. The extreme phenotype study design will be used to enrich the cases by family history of CRC and/or early age of onset. This enrichment of genetic component in the cases will enable us to have sufficient power to identify potential disease causing rare variants with th current sample size. For rare variants (MAF < 5%), we will employ the gene-based approach to facilitate identification of rare variants associated with the risk of CRC. The second aim is to internally validate the top 1,000 genes by targeted sequencing in an additional 4,400 samples from MD Anderson. The third aim is to externally validate the top 100 genes in an additional 1,500 samples from University of Utah and further examine these 100 genes in 400 African American (AA) CRC cases and 400 AA Controls and 400 Hispanic American (HA) cases and 400 HA controls from MD Anderson by targeted sequencing. The fourth aim is to build quantitative risk prediction model by incorporating epidemiologic factors, exposure factors, and genetic factors for the risk of CRC. This study will provide significant insight in the etiology of CRC and improve our understandings of the genetic basis of CRC. The prediction model will enable us to identify genetically susceptible individuals at high-risk of developing CRC who would benefit from intensive screening and/or chemopreventive interventions. It is of immense clinical and public health benefit.